Acceptance of allografts in humans currently requires long-term morbid therapy with immunosuppressive drugs. The development of brief, elegant, and specific therapies to induce tolerance is a highly desirable goal. Achievement of tolerance in transplantation will require an understanding of the complex mechanisms of T cells, which generate allograft injury. The second signal in T cell activation is mediated through engagement of one or more costimulatory molecules, and targeting such pathways has been successful in preventing allograft rejection and occasionally in inducing tolerance in certain models of transplantation. The recently discovered inducible costimulatory molecule (ICOS) is the newest member of the CD28 family of T cell membrane proteins. When ligated to its receptor, B7-homolog (B7-h), ICOS provides a signal which enhances T cell expansion. ICOS appears to be critical for production of certain cytokines, T cell differentiation, and CD 154 dependent B cell Ig isotype class switching. This project is designed to determine the importance of ICOS-B7h signaling in the development of allograft injury in two models of acute rejection and one model of chronic allograft vasculopathy. Furthermore, the specific mechanisms by which ICOS participates in alloimmune injury will be dissected, essentially thorough study of the behavior of the immune response in the presence and absence of ICOS signaling. As a small part of a larger body of work, this research has potential to elucidate clinically important treatment strategies.